Merck expects to file Biologics License Application with U.S. FDA
in 2013

November 04, 2013 07:30 AM Eastern Standard Time

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada,
announced today that in the pivotal Phase III efficacy study, its
investigational 9-valent HPV vaccine (V503) prevented approximately 97
percent of cervical, vaginal and vulvar pre-cancers caused by HPV types
31, 33, 45, 52, and 58. V503 also generated immune responses to HPV
types 6, 11, 16, and 18 that were non-inferior to those generated by
GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11,
16, and 18) Vaccine, Recombinant]. V503 includes five more HPV types
(31, 33, 45, 52, 58) in addition to the four original HPV types (6, 11,
16, 18) in GARDASIL. These data, along with results of two other Phase
III studies, will be presented for the first time at the European
Research Organisation on Genital Infection and Neoplasia (EUROGIN)
Congress during a late-breaker oral session on Tuesday, November 5.

Results from the pivotal Phase III efficacy study (abstract #SS 8-4)

The pivotal Phase III study (Protocol 001) evaluated the efficacy,
safety and immunogenicity of V503 (n=7,099) compared to GARDASIL
(n=7,105) in 16-26-year old females. The primary efficacy analysis was
conducted in those who received all three doses of vaccine within one
year, who were not infected with the relevant HPV types at enrollment
and who remained free of infection with the relevant HPV types through
Month 7 (per-protocol population). The results were as follows:

97.1 percent reduction (95% CI; 91.8, 99.2) in the combined incidence
of cervical/vulvar/vaginal disease of any grade (all CIN, VIN, VaIN)
caused by HPV types 31, 33, 45, 52, 58 (3 cases in the group that
received V503 vs. 103 cases in the group that received GARDASIL).

96.0 percent efficacy (95% CI; 94.4, 97.2) against six-month
persistent HPV infection with HPV types 31, 33, 45, 52, 58 (35 cases
in the group that received V503 vs. 810 cases in the group that
received GARDASIL).

Because GARDASIL does not contain the five additional HPV types in V503,
cases of disease caused by these five types in the study group that
received GARDASIL were expected.

“In the Phase III studies being presented for the first time, V503
prevented approximately 97 percent of high-grade cervical, vulvar and
vaginal diseases caused by five additional HPV types,” said Elmar Joura,
M.D., Associate Professor of Gynecology and Obstetrics, Medical
University of Vienna and Comprehensive Cancer Center, Vienna, Austria,
and study investigator who will present these results at EUROGIN.

Non-inferior immunogenicity for the four HPV types (6, 11, 16, 18) also
in GARDASIL was a second primary endpoint in this study. Because
GARDASIL has been shown in clinical studies to be highly effective
against certain diseases caused by HPV types 6, 11, 16, and 18, few
disease endpoints caused by these HPV types were expected, making it
difficult to directly assess efficacy of V503 for these four types.
Therefore, antibody levels were evaluated for these four HPV types
common to both vaccines. V503 generated immune responses for HPV 6, 11,
16, and 18 (measured by geometric mean titers (GMTs) and seroconversion
rates at Month 7) that were non-inferior to those generated by GARDASIL.
In the study, the seroconversion rates were 99.8 percent for HPV types 6
and 18 and 100 percent for HPV types 11 and 16 in the V503 group. The
corresponding numbers in the group that received GARDASIL were 99.8,
99.9, 100, and 99.7 percent for HPV types 6, 11, 16 and 18,
respectively. These results are to support the bridging of the efficacy
findings for GARDASIL for HPV types 6, 11, 16, 18 to V503.

“Our investigational vaccine V503 reduced HPV-associated precancerous
lesions in young women,” said Roger M. Perlmutter, M.D., Ph.D.,
president of Merck Research Laboratories. “With our ongoing commitment
to research, we are building upon the success obtained with GARDASIL,
and we expect to submit a Biologics License Application for V503 to the
U.S. Food and Drug Administration before the end of 2013.”

Also presented at EUROGIN were results from two open-label
immunobridging studies for V503 in adolescents. Immunobridging studies
were used for the adolescent population because adolescents are not
likely to have been exposed to HPV, and therefore, efficacy against
disease endpoints cannot be studied directly. Immunogenicity ‘bridging
data’ is an accepted surrogate for efficacy and is an approach that is
accepted by major regulatory agencies.

In Protocol 002, which is aimed at extending the pivotal efficacy study
findings in females 16-26 years of age to males and females 9-15 years
of age (adolescents), 3,074 subjects were divided into three groups –
669 male 9-15-year olds, 1,935 female 9-15-year olds and 470 female
16-26-year olds. Immune responses to V503 were compared among the
groups. All study participants in the per-protocol population received
three doses of V503 over a six-month period and were evaluated at month
7 for GMTs and seroconversion rates. Results from this study showed
non-inferior immunogenicity of V503 in adolescent males and females
compared with females 16-26 years old for all nine vaccine HPV types:
99.8-100 percent of adolescent females and 99.8-100 percent of
adolescent males seroconverted, or developed antibodies, against the
nine HPV types at month 7 compared to 99.5-100 percent of 16-26-year old
females. The safety profile of V503 was similar or slightly more
favorable in adolescent males compared to adolescent females and females
16-26 years old; the overall safety and tolerability findings were
consistent with those reported in previous studies with GARDASIL [Human
Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine,
Recombinant].

In Protocol 009, 600 adolescent females who had not yet received a
prophylactic HPV vaccine were randomized into two groups – 300 who
received V503 and 300 who received GARDASIL – to compare the immune
responses in adolescent girls for HPV types 6, 11, 16 and 18. All study
participants in the per-protocol population received three doses of
GARDASIL or V503 over a six-month period and were evaluated at month 7
for GMTs and seroconversion rates. In this study, immunogenicity of V503
was non-inferior compared to GARDASIL in adolescent females for HPV
types 6, 11, 16 and 18: 100 percent of adolescent females in both study
groups seroconverted against HPV types 6, 11, 16 and 18 at month 7. The
overall safety profile of V503 was generally similar to GARDASIL, with
higher frequency of injection-site swelling with V503.

GARDASIL is indicated in the United States for use in girls and young
women 9 through 26 years of age for the prevention of cervical, vulvar,
vaginal and anal cancers caused by HPV types 16 and 18; genital warts
caused by HPV types 6 and 11; and precancerous or dysplastic lesions
caused by HPV types 6, 11, 16 and 18. GARDASIL is also approved for use
in boys and men 9 through 26 years of age for the prevention of anal
cancer caused by HPV types 16 and 18; genital warts caused by HPV types
6 and 11; and precancerous or dysplastic lesions caused by HPV types 6,
11, 16 and 18.

Important information about GARDASIL

GARDASIL does not eliminate the necessity for women to continue to
undergo recommended cervical cancer screening. Recipients of GARDASIL
should not discontinue anal cancer screening if it has been recommended
by a health care provider.

GARDASIL has not been demonstrated to provide protection against
diseases from vaccine and non-vaccine HPV types to which a person has
previously been exposed through sexual activity.

GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18)
Vaccine, Recombinant] has not been demonstrated to protect against
disease due to HPV types not contained in the vaccine.

Not all vulvar, vaginal and anal cancers are caused by HPV, and GARDASIL
protects only against those vulvar, vaginal and anal cancers caused by
HPV Types 16 and 18.

Select safety information for GARDASIL

GARDASIL is contraindicated in individuals with hypersensitivity,
including severe allergic reactions to yeast, or after a previous dose
of GARDASIL.

Because vaccinees may develop syncope, sometimes resulting in falling
with injury, observation for 15 minutes after administration is
recommended. Syncope, sometimes associated with tonic-clonic movements
and other seizure-like activity, has been reported following vaccination
with GARDASIL. When syncope is associated with tonic-clonic movements,
the activity is usually transient and typically responds to restoring
cerebral perfusion.

GARDASIL is not recommended for use in pregnant women.

The most common adverse reaction was headache. Common adverse reactions
that were observed among recipients of GARDASIL at a frequency of at
least 1.0 percent and greater than placebo were: fever, nausea,
dizziness; and injection-site pain, swelling, erythema, pruritus and
bruising.

Dosage and administration for GARDASIL

GARDASIL is a ready-to-use, three-dose, intramuscular vaccine. GARDASIL
should be administered in three separate intramuscular injections in the
deltoid region of the upper arm or in the higher anterolateral area of
the thigh. The following dosage schedule is recommended: first dose at
elected date, second dose two months after the first dose and the third
dose six months after the first dose.

About HPV and cancer

Human papillomavirus (HPV) causes virtually all cervical cancer cases
and also causes some cases of vulvar and vaginal cancer in females, and
anal cancers and genital warts in both females and males. Cervical
cancer is the third most common type of cancer among women worldwide. It
is estimated that approximately 530,000 women develop cervical cancer
annually around the world, with about 85 percent of cases occurring in
developing countries.

The seven cancer-causing HPV types in V503 (16, 18, 31, 33, 45, 52 and
58) cause approximately 90 percent of cervical cancer cases,
approximately 80 percent of high-grade cervical dysplasias (cervical
precancers) worldwide, and approximately 50-60 percent of cases of
low-grade cervical dysplasias. These seven HPV types also can cause
vaginal, vulvar and anal cancers and pre-cancers. After HPV types 16 and
18, the five additional HPV types in V503 are the most common cervical
cancer-causing types worldwide. HPV types 6 and 11 cause approximately
90 percent of genital warts cases.

About Merck

Today's Merck is a global healthcare leader working to help the world be
well. Merck is known as MSD outside the United States and Canada.
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solutions. We also demonstrate our commitment to increasing access to
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